Inhibitors of HIV integrase are being developed as potential anti-AIDS drugs. In preliminary studies approximately 30 compounds have been prepared as HIV integrase inhibitors based on the structural lead provided by caffeic acid phenethyl ester (CAPE, IC50 = 7 microM). Among the features examined for their effects on inhibitory potency were ring substitution, side chain length and composition and phenyl ring conformational orientation. Ortho-hydroxyl substitution was found to be a consistent requirement for inhibitory potency throughout the series. Three analogues were found to be "moderately active" in the NCI cell- based AIDS assay, with no obvious correlation with integrase inhibitory potency being apparent for these compounds. Structure-activity studies are continuing on a series of hydroxylated phenethylamide analogues of 3-phenylpropionic acid. Additional synthetic studies are in progress using coumarin pharmacophores found to have activity both as integrase inhibitors and in the cell-based anti-AIDS screen. The application of combinatorial chemistry for the generation of inhibitor libraries is being investigated. Computer assisted molecular modeling will also be utilized to systematically analyze structure activity results, as well as the subsequent design of new synthetic targets.